We will take a new approach to harness dendritic cell (DC) biology to improve vaccine design for SIV and HIV. We will pursue recent advances in mice involving antigen uptake, processing and maturation by DCs in situ. Vaccines will be targeted to monkey and human DCs by engineering antigens into antibodies to uptake receptors that are selectively expressed by DCs in lymphoid organs, e.g., DEC-205. Antibody targeting to DEC-205 enhances antigen presentation in mice 100-1000 fold to both CD4 + and CD8 + T cells. When this targeting is coupled with a DC maturation stimulus, mice develop unusually strong and long lasting effector T cell responses, i.e., Th1 type CD4 + T cells and cytolytic CD8 + T cells. The responses are much greater than prior "gold standards," like complete Freund's adjuvant. The mice resist challenge to antigen in recombinant vaccinia virus delivered via the lung and growing tumors in the skin. We will move this vaccine strategy into monkeys and human, using a new monoclonal reactive with monkey/human DEC-205, which is expressed at high levels on DCs in human and monkey lymph nodes and spleen. The heavy chains of anti-DEC-205 antibodies have already been engineered to express several peptides and HIV gag p24 protein. We will verify that anti-human DEC-205 mediates efficient presentation of engineered antigens on the MHC class I and II products of human DCs. We will simultaneously compare several methods for maturing DCs in vivo in mice, to achieve optimal presentation and strong effector and memory T cell responses after targeting by anti-DEC- 205: antigen conjugates. We will engineer microbial proteins, not just peptides, into DEC-205 antibodies to test that human and monkey DCs present viral proteins including proteins from HIV and SIV gag proteins. Then we can begin to immunize macaques with engineered, DC-targeting antibody plus a maturation stimulus, to assess combined CD4 + and CD8 + T cell immunity and memory. In this way the concepts of antigen targeting coupled with DC maturation can be assessed as a new vaccination strategy for nonhuman primates.